Method and apparatus for transferring a defined quantity of powder

ABSTRACT

There is provided a method of transferring a defined quantity of powder comprising compacting a target area of powder; dipping a tube into the compacted target area of powder to fill the tube with a defined volume of powder; and transferring the defined volume of powder from the tube.

This application is filed pursuant to 35 USC 371 as a United StatesNational Phase Application of International Patent Application Ser. No.PCT/EP01/06196 filed 31 May 2001, which claims priority from GB0014082.2 filed on Jun. 10, 2000 in the United Kingdom.

FIELD OF INVENTION

This invention relates to a method and apparatus for transferring adefined quantity of pre-compacted powder. This invention has particularapplication to transferring a defined quantity of powdered medicamentinto a pack, for example a blister pack, for use in a drug deliverysystem such as an inhalation device.

BACKGROUND TO THE INVENTION

The use of dosating apparatus to measure and transfer a defined volumeof powder is well known. Typically the dosating apparatus comprises adosator piston located in a sleeve, the dosator piston being retractablewithin the sleeve to create a cavity. The dosating apparatus is loweredinto a powder reservoir to collect a sample of powder in the cavity andthe powder is then ejected from the cavity into a suitable container.

Some of the problems involved in such a process concern optimisation ofthe fill accuracy and reproducibility, and reducing the aeration of thepowder. Improvements to the dosating process made by prior art systemshave typically involved either compacting the powder contained in thecavity or ensuring that air does not enter the cavity when filling.Compacting the powder when in the sleeve only compacts and reduces insize the sample already removed, improving packing but not the actualaccuracy of the dose. Ensuring that air does not enter the cavity as theapparatus is lowered into the powder by retracting the dosator piston asthe apparatus moves through the powder bed improves the filling to acertain extent but the density of the powder in the bed is not altered.A vacuum in the bottom of a powder reservoir may be used to improve theuniformity of the density of the bed. However, when the powder comprisesa medicament and an excipient, the medicament particles are strippedfrom the excipient by the vacuum and a filter is required to capture themedicament particles.

The Applicants have found that the dose to dose repeatability andaccuracy of the filling process can be improved by compacting the powderin the reservoir prior to removing the dose of powder to improve theuniformity of the density of the bed and to remove air from the bed.Compacting the powder in the bed prior to removing a sample has theadvantage that the powder under the target is free to move within andaway from the target area if necessary, leading to production of a bedwith a more uniform density to ensure that all samples removed are ofequal size.

The whole bed may be compacted prior to removal of the sample powder oralternatively small local areas of the bed may be compacted,corresponding to the area which will be removed. Compacting local areasof the bed has the advantage that the bed is easier to disrupt andprepare for the next round of sampling.

SUMMARY OF THE INVENTION

According to the invention there is provided a method of transferring adefined quantity of powder comprising:

-   -   a) compacting a target area of powder;    -   b) dipping a tube into said compacted target area of powder to        fill said tube with a defined volume of powder; and    -   c) transferring said defined volume of powder from said tube.

Preferably the powder is compactable to between 10 and 99% of itsoriginal density. More preferably the powder is compactable to between20 and 50% of its original density.

In one aspect of the invention the compaction is achievable by the useof a compaction pin.

In another aspect the compaction is achievable by the use of acompaction plate. The plate may compact the target area of powder or maycompact the whole powder bed.

In a further aspect the compaction is achievable by the use of a dosatorpiston located within the tube such that it protrudes from the dippingend of the tube.

In a further aspect the compaction is achievable by the use of a dosatorpiston located within the tube such that it is essentially flush withthe dipping end of the tube. By essentially flush it is meant that thedosator piston is preferably flush with the dipping end of the tube,however small variations in the position of the dosator piston withrespect to the dipping end of the tube may be envisaged.

Preferably said dosator piston is slidably retractable within the tubefollowing compaction to create a cavity for filling with the definedvolume of powder. The dosator piston is retractable by a pre-determineddistance to allow for precise metering of compacted powder.

Preferably the tube is tapered towards its dipping end.

Preferably the target area of powder is greater than the inner crosssectional area of the tube. Alternatively the target area of powder isequal to the inner cross sectional area of the tube.

The invention further comprises compacting the powder in the tubesubsequent to filling the tube with the defined quantity or volume ofpowder. The dosator piston is initially retracted within the tube tocreate a larger cavity than usually required. After filling the cavityis then reduced in size to compact the powder within the tube. Thisextra step may have an advantage when a small container is required tobe filled with an increased amount of powder.

Preferably the defined volume of powder is transferable from the tube byslidable movement of the dosator piston to eject the powder. The dosatorpiston is moved within the tube to reduce the size of the cavity untilthe dosator piston is at least flush with the dipping end of the tube orprotruding.

Preferably the method additionally comprises transferring the powder toa container. Preferably the container is selected from the groupconsisting of a blister pocket, an injection moulded plastic pocket anda capsule. The filled tube is raised out of the powder bed and alignedwith the container before the powder is ejected.

An additional component of the invention comprises applying a seal toeach end of the filled tube, subsequent to dipping the tube into thecompacted target area of powder.

A further additional component of the invention comprises placing saidsealed tube in a drug delivery system. Suitable drug delivery systemsinclude inhalation devices used to deliver powdered medicament.

A further additional component of the invention comprises piercing saidseal immediately prior to transferring the defined volume of powder.

Preferably the piercing is achievable by the use of a piercing pin.

Preferably said piercing pin forms an integral part of said drugdelivery system.

Preferably the defined volume of powder is transferable from said tubeby use of a transferring pin to eject the powder into the drug deliverysystem. The powder is then ready for immediate inhalation by the patientand the empty tube may be disposed of.

Preferably said transferring pin forms an integral part of the drugdelivery system.

Preferably the piercing pin and the transferring pin are identical.

An additional component of the invention comprises levelling the powderprior to compaction.

Preferably the levelling is achieved by the use of a leveller blademovable on a linear sweeping path.

In one aspect said leveller blade is perpendicular to said linearsweeping path.

In another aspect the leveller blade presents a forward acute angle tothe linear sweeping path. That is to say, the angle between thedirection of the sweeping path and the blade is less than 90°.Preferably the forward acute angle is between 1 and 60°. More preferablythe forward acute angle is between 40 and 50°.

Alternatively, a curved or articulated blade or a blade presenting anobtuse angle to the linear path may be used to level the powder.Optionally the blade may be passed through the powder bed more thanonce. The number of passes of the blade through the bed can be variedaccording to the properties of the powder. Alternatively multiple bladesmay be used to level the powder.

An additional component of the invention comprises disrupting the powderfollowing removal of the defined quantity or volume of powder.

Preferably the powder comprises a medicament. Preferably the medicamentis selected from the group consisting of albuterol, salmeterol,fluticasone propionate and beclomethasone dipropionate and salts orsolvates thereof and any mixtures thereof. Preferably said mixturecomprises a combination of salmeterol xinafoate and fluticasonepropionate.

Preferably the powder further comprises an excipient. Preferably theexcipient is a sugar. A suitable sugar comprises lactose.

Alternatively the powder is selected from the group consisting ofexplosive powder, powdered sweeteners, powdered herbal products,powdered food supplements and vitamins. The explosive powders aresuitable for use in munitions or in pyrotechnics.

According to the invention there is also provided an apparatus fortransferring a defined quantity of powder which comprises;

-   -   a) a powder reservoir;    -   b) a compactor for compacting a target area of powder;    -   c) a tube suitable for containing a defined volume of powder;        and    -   d) a transferor to transfer said defined volume of powder from        said tube.

By powder reservoir it is meant a container suitable for containingpowder.

In one aspect of the invention the compactor comprises a compaction pin.

In another aspect the compactor comprises a compaction plate.

In a further aspect the compactor comprises a dosator piston locatedwithin the tube such that it protrudes from the dipping end.

In an alternative aspect the compactor comprises a dosator pistonlocated within the tube such that it is essentially flush with thedipping end. By essentially flush it is meant that the dosator piston ispreferably flush with the dipping end of the tube, however smallvariations in the position of the dosator piston with respect to thedipping end of the tube may be envisaged.

Preferably said dosator piston is slidably retractable within the tubeto create a cavity for filling with the defined volume of powder. Thedosator piston is retractable by a pre-determined distance to allow forprecise metering of compacted powder.

Preferably the tube is tapered towards its dipping end.

Preferably the target area of powder is greater than the inner crosssectional area of the tube. Alternatively the target area of powder isequal to the inner cross sectional area of the tube.

An additional component of the invention comprises a seal applier toapply a seal to each end of the filled tube, subsequent to dipping thetube into the compacted target area of powder.

A further additional component of the invention comprises a loader toload drug delivery system with said sealed tube. Suitable drug deliverysystems include inhalation devices used to deliver powdered medicaments.

A further additional component of the invention comprises a piercer topierce said seal immediately prior to transferring the defined volume ofpowder.

Preferably the piercer comprises a piercing pin. Preferably saidpiercing pin forms an integral part of said drug delivery system.

Preferably the transferor comprises a transferring pin. The transferringpin is inserted into the tube to eject the powder into the drug deliverysystem. The powder is then ready for immediate inhalation by the patientand the empty tube may be disposed of.

Preferably said transferring pin forms an integral part of the drugdelivery system.

Preferably the transferring pin and piercer pin are identical.

In one aspect of the invention the transferor transfers the definedvolume of powder to a container. Preferably the container is selectedfrom the group consisting of a blister pocket, an injection mouldedplastic pocket and a capsule. The filled tube is raised out of thepowder bed and aligned with the container before the powder istransferred. Preferably the transferor comprises the dosator pistonwhich slidably moves within the tube to eject the powder. The dosatorpiston is slidably moved until it is at least flush with the dipping endof the tube or protruding from it.

An additional component of the invention comprises a leveller to levelthe powder prior to compaction.

Preferably the levelling is achieved by the use of a leveller blademovable on a linear sweeping path.

Preferably said leveller blade is perpendicular to said linear sweepingpath.

Alternatively the leveller blade presents a forward acute angle to thelinear sweeping path. That is to say, the angle between the direction ofthe sweeping path and the blade is less than 90°. Preferably the forwardacute angle is between 1 and 60°. More preferably the forward acuteangle is between 40 and 50°.

Alternatively, a curved or articulated blade or a blade presenting anobtuse angle to the linear path may be used to level the powder.Optionally the blade may be passed through the powder bed more thanonce. The number of passes of the blade through the bed can be variedaccording to the properties of the powder. Alternatively multiple bladesmay be used to level the powder.

An additional component of the invention comprises a disrupter todisrupt the powder following removal of the defined quantity of powder.

Preferably the powder comprises a medicament. Preferably the medicamentis selected from the group consisting of albuterol, salmeterol,fluticasone propionate and beclomethasone dipropionate and salts orsolvates thereof and any mixtures thereof. Preferably said mixturecomprises a combination of salmeterol xinafoate and fluticasonepropionate.

Preferably the powder further comprises an excipient. Preferably theexcipient is a sugar. A suitable sugar comprises lactose.

Alternatively the powder is selected from the group consisting ofexplosive powder, powdered sweeteners, powdered herbal products,powdered food supplements and vitamins. The explosive powders aresuitable for use in munitions or in pyrotechnics.

The invention also provides a transferred powder sample obtainable bythe method as herein described.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described with reference to the accompanyingdrawings in which:

FIGS. 1 a and 1 b show compaction stages in accord with the presentinvention;

FIGS. 1 c and 1 d show filling stages subsequent to the compactionstages in FIGS. 1 a and 1 b in accord with the present invention;

FIGS. 1 e, 1 f and 1 g show the powder transfer stages subsequent to thefilling stage shown in FIGS. 1 c and 1 d;

FIGS. 2 a and 2 b show an alternative compaction stage to FIGS. 1 a and1 b in accord with the present invention;

FIGS. 3 a, 3 b and 3 c show an alternative filling stage to FIGS. 1 cand 1 d in accord with the present invention;

FIGS. 4 a and 4 b show an alternative compaction stage to that shown inFIGS. 1 a and 1 b in accord with the present invention;

FIGS. 5 a, 5 b and 5 c show a filling stage subsequent to FIGS. 4 a and4 b or alternative to that shown in FIGS. 1 c and 1 d or in FIGS. 3 a, 3b and 3 c in accord with the present invention;

FIG. 6 a shows a multi-dose system in accord with the present invention;and

FIGS. 6 b and 6 c shows the transfer stages subsequent to FIG. 6 a inaccord with the present invention.

FIG. 6 d depicts shows an alternative embodiment wherein the tube issealed.

FIGS. 7 a and 7 b show alternative transfer stages to those shown inFIGS. 6 b and 6 c in accord with the present invention.

FIG. 8 depicts the action of a disrupter in accord with the presentinvention.

FIG. 9 shows a levelling stage subsequent to the transfer stages inaccord with the present invention.

DETAILED DESCRIPTION OF THE DRAWINGS

FIGS. 1 a to 1 g show a complete cycle for transferring a definedquantity of powder comprising compaction, filling and transfer. Dosatorpiston 10 is located in sleeve 20 such that the dosator piston 10 isflush with the dipping end 22 of the sleeve 20 (FIG. 1 a). The sleeve 20and its internal bore may be of any shape in cross-section (e.g.circular, square, rectangular, hexagonal) provided the bore and pistonare of the same cross-sectional shape and that the piston 10 fits snuglywithin and against the walls of the bore. The dosator piston 10 andsleeve 20 are lowered into the reservoir of powder 30 and the dosatorpiston 10 compacts the area of powder 30 that it contacts (FIG. 1 b).Dosator piston 10 is retracted up the sleeve 20 to create a cavity 40(FIG. 1 c). The dosator piston 10 and sleeve 20 are then moved downthrough the compacted powder 30 to force a defined quantity or volume(or dose) 32 of the compacted powder 30 into the cavity 40 (FIG. 1 d).Dosator piston 10, sleeve 20 and the defined volume 32 of compactedpowder 30 in the cavity 40 are then raised out of the reservoir ofpowder 30 (FIG. 1 e) and brought into registration with a container 50,for example a blister pocket of a blister pack (FIG. 1 f). Finally,dosator piston 10 is moved towards the dipping end 22 of the sleeve 20to eject the defined quantity or volume 32 of powder 30 from the cavity40 (FIG. 1 g) into the blister pocket 50.

It will be understood that a number of means can be utilised to removeexcess powder from the external edges of the dipping end 22 of thesleeve 20 once cavity 40 has been filled with powder 30. These includethe use of stripper wire(s) (not shown) or blade(s) (not shown) whichmay be suspended above the reservoir of powder 30 and wiped against theexternal edges of the dipping end 22 by movement of the wire or bladeacross the edge. An alternative method involves rotating the dipping end22 of the sleeve 20 relative to the reservoir of powder 30 when thedipping end 22 is immersed in the reservoir.

FIGS. 2 a and 2 b show an alternative compaction stage to that shown inFIGS. 1 a and 1 b. Dosator piston 110 is located in sleeve 120 such thatthe dosator piston 110 protrudes from the dipping end 122 of the sleeve120 (FIG. 2 a). The dosator piston 110 and sleeve 120 are lowered intothe reservoir of powder 130 and the dosator piston 110 compacts the areaof powder 130 that it contacts (FIG. 2 b).

FIGS. 3 a, 3 b and 3 c show an alternative filling stage to FIGS. 1 cand 1 d. Dosator piston 210 is retracted up the sleeve 220 followingcompaction of the powder, to create a cavity 240 (FIG. 3 a). The cavity240 is larger than that of the cavity 40 in FIG. 1 c. The dosator piston210 and sleeve 220 are then moved down through the compacted powder 230to force the powder into the cavity 240 (FIG. 3 b). Dosator piston 210is then moved relative to the sleeve 220 to reduce the size of thecavity 240 (FIG. 3 c). This has the effect of further compacting thedefined quantity or volume 232 of powder 230 in the cavity 240. Theprocess then continues with transfer steps as shown in FIGS. 1 e, 1 fand 1 g.

It will be understood that an alternative form of filling cavity 240with powder 230 involves lowering the dipping end 222 of the sleeve 220into the reservoir of powder 230 and pushing powder 230 into the cavity240 from below (not shown). Compaction pins (not shown) positioned atthe base of the reservoir of powder 230, and below the sleeve 220, couldpush powder 230 into cavity 240.

FIGS. 4 a and 4 b show an alternative compaction process to that shownin FIGS. 1 a and 1 b or 2 a and 2 b. A compaction pin 360 is loweredinto the reservoir of powder 330 to compact the area of powder 330 thatit contacts (FIG. 4 a). The compaction pin 360 is then raised out of thepowder 330 and the process can then continue using a dosator piston 310in a sleeve 320 as shown in FIGS. 1 c to 1 g.

FIGS. 5 a, 5 b and 5 c show an alternative to the process shown in FIGS.1 c to 1 e. The compaction pin 460 is lowered into the sleeve 420 tocreate a cavity 440 for filling with a defined volume of powder 430(FIGS. 5 a and 5 b). The compaction pin 460 and sleeve 420 are thenlowered into the reservoir of powder 430 to fill the cavity 440 withcompacted powder 430 (FIG. 5 c). The process can then continue byremoving the compaction pin 460 and sleeve 420 from the reservoir ofpowder 430 and using the compaction pin 460 to eject the powder 432 fromthe cavity 440 into a container (not shown) as shown in FIGS. 1 e to 1 gfor a dosator piston.

It should be appreciated that the dosator pistons, compaction pins andsleeves shown in the above figures may form part of a multi-dosingsystem with multiples of these apparatus components all operatingsimultaneously to remove defined quantities of powder for transfer.

FIG. 6 a shows an example of a multi-dosing system. The system comprisesdosator pistons 510 a, 510 b, 510 c located in tubes 520 a, 520 b and520 c which are joined together at their upper portions.

The compaction and filling stages take place in the multi-dose system asshown in FIGS. 1 b to 1 d for a single dosing system. The tubes 520 a,520 b and 520 c and dosator pistons 510 a, 510 b, 510 c are lowered intothe powder reservoir to compact individual areas of powder. The dosatorpistons 510 a, 510 b, 510 c are then retracted up the tubes 520 a, 520 band 520 c to create a cavity in each tube 520 a, 520 b and 520 c and thesystem is then lowered further into the powder to fill the cavity withcompacted powder.

Alternatively, multiple compaction pins may be used to compact thepowder and may then either be assembled into the tubes to create acavity for filling with powder as shown in FIGS. 5 a, 5 b and 5 c or maybe replaced by dosator pistons located within the tubes.

The filled tubes 520 a, 520 b, 520 c are shown in FIG. 6 b when theyhave been raised out of the powder reservoir 530. Seals may be appliedto the ends of the tubes 520 a, 520 b, 520 c at this stage to retain thepowder in the tubes 520 a, 520 b, 520 c. The tubes 520 a, 520 b, 520 cmay then be assembled into a drug delivery system, such as an inhalationdevice (not shown).

When a dose 532 of powder is required, the dosator piston 510 a, 510 b,510 c may be used to eject the defined quantity or volume 532 of powder530 into the inhalation device for inhalation by the patient (FIG. 6 c).

Alternatively, the dosator pistons may be removed from the tubes 620 a,620 b, 620 c to leave the defined volume of powder 632 occupying aportion of the tubes 620 a, 620 b, 620 c and an empty space 660 in therest of the tube 620 a, 620 b, 620 c (FIG. 7 a). An ejector pin 670which may form an integral part of the inhalation device (not shown),may be inserted into the empty space 660 in one tube 620 c to eject thedefined quantity or volume of powder 632 into the inhalation device forinhalation by the patient (FIG. 7 b). The ejector pin 670 may be used topierce any seals 570 a. 570 b and 570 c (as shown in FIG. 6 d) appliedvia seal applier 580 to the tubes 620 a, 620 b, 620 c or a separatepiercing device may be used. The tubes 620 a, 620 b, 620 c may bedisposed of after the powder dose has been removed.

After removal of the defined volume of powder from the powder reservoirthe remaining powder is disrupted using a disrupter so that the holesleft following powder removal are filled in (FIG. 8). Suitable means ofdisrupting the powder reservoir include the use of a disruptor blade 780or paddle which can be plunged into the powder reservoir 730 and movedthroughout it (e.g. in the direction of the arrow in FIG. 8) to leave amore regular bed 735 of powder. In an alternative method, the reservoirof powder is moved relative to the immersed blade or paddle. Anothermethod (not shown) includes plunging a circular or U-shaped wire intothe reservoir and moving it (or the reservoir) in a rotational orlongitudinal direction to disrupt the powder.

The disrupted bed is then levelled using a leveller blade or othersuitable leveller. A leveller blade 885 is shown in FIG. 9. The blade885 is shown mounted at an angle of approximately 45° to the bottom ofthe powder bed 838 and depicts one possible configuration of the blade885 in accord with the present invention. It should however beappreciated that the leveller blade 885 may be mounted at any anglewithin a wide range, typically (but not exclusively) at an acute angleand preferably between 1 and 60°, and may be varied according to theproperties of the powder 830 to optimise powder levelling. When theblade is angled at an acute angle it exerts a compressive force on thepowder which produces a powder bed with a more uniform density thanusing a perpendicular blade. However, it is also possible to use bladesthat are perpendicular or mounted at an obtuse angle. It should beappreciated that curved or articulated blades may alternatively be used.The tail sections of the leveller blade are not essential to the blade'saction although they may also be angled and exert a further compressiveforce on the powder.

The invention is suitable for filling blister packs or other suitablecontainers with powdered medicament, particularly for the treatment ofrespiratory disorders. The invention is also suitable for filling tubeswith powdered medicament for the treatment of respiratory disorders tobe used in a drug delivery system (e.g. an inhalation device).

Appropriate medicaments may thus be selected from, for example,analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl ormorphine; anginal preparations, e.g., diltiazem; antiallergics, e.g.,cromoglycate (e.g. s the sodium salt), ketotifen or nedocromil (e.g. asthe sodium salt); antiinfectives e.g., cephalosporins, penicillins,streptomycin, sulphonamides, tetracyclines and pentamidine;antihistamines, e.g., methapyrilene; anti-inflammatories, e.g.,beclomethasone (e.g. as the dipropionate ester), fluticasone (e.g. asthe propionate ester), flunisolide, budesonide, rofleponide, mometasonee.g. as the furoate ester), ciclesonide, triamcinolone (e.g. as theacetonide) or 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester; antitussives, e.g.,noscapine; bronchodilators, e.g., albuterol (e.g. as free base orsulphate), salmeterol (e.g. as xinafoate), ephedrine, adrenaline,fenoterol (e.g. as hydrobromide), formoterol (e.g. as fumarate),isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol (e.g. as acetate), reproterol (e.g. as hydrochloride),rimiterol, terbutaline (e.g. as sulphate), isoetharine, tulobuterol or4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone;adenosine 2a agonists, e.g.2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol(e.g. as maleate); α₄ integrin inhibitors e.g.(2S)-3-[4-({[4-(aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino]propanoicacid (e.g. as free acid or potassium salt), diuretics, e.g., amiloride;anticholinergics, e.g., ipratropium (e.g. as bromide), tiotropium,atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone orprednisolone; xanthines, e.g., aminophylline, choline theophyllinate,lysine theophyllinate or theophylline; therapeutic proteins andpeptides, e.g., insulin or glucagon; vaccines, diagnostics, and genetherapies. It will be clear to a person skilled in the art that, whereappropriate, the medicaments may be used in the form of salts, (e.g., asalkali metal or amine salts or as acid addition salts) or as esters(e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimisethe activity and/or stability of the medicament.

Preferred medicaments are selected from albuterol, salmeterol,fluticasone propionate and beclomethasone dipropionate and salts orsolvates thereof, e.g., the sulphate of albuterol and the xinafoate ofsalmeterol.

Medicaments can also be delivered in combinations. Preferredformulations containing combinations of active ingredients containsalbutamol (e.g., as the free base or the sulphate salt) or salmeterol(e.g., as the xinafoate salt) or formoterol (e.g. as the fumarate salt)in combination with an antiinflammatory steroid such as a beclomethasoneester (e.g., the dipropionate) or a fluticasone ester (e.g., thepropionate) or budesonide. A particularly preferred combination is acombination of fluticasone propionate and salmeterol, or a salt thereof(particularly the xinafoate salt). A further combination of particularinterest is budesonide and formoterol (e.g. as the fumarate salt).

It may be appreciated that any of the parts of the apparatus thatcontact the powder may be coated with materials such as fluoropolymermaterials which reduce the tendency of medicament to adhere thereto.Suitable fluoropolymers include polytetrafluoroethylene (PTFE) andfluoroethylene propylene (FEP). Any movable parts may also have coatingsapplied thereto which enhance their desired movement characteristics.Frictional coatings may therefore be applied to enhance frictionalcontact and lubricants used to reduce frictional contact as necessary.

It will be understood that the present disclosure is for the purpose ofillustration only and the invention extends to modifications, variationsand improvements thereto.

The application of which this description and claims form part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described therein. They may take the form ofproduct, method or use claims or may include, by way of example andwithout limitation, one or more of the following claims:

1. A method of transferring a defined quantity of powder comprising: a)compacting, within a bed of powder, a target area without compacting theentirety of the bed of powder surrounding the target area of powder; b)dipping a tube into said compacted target area of powder to fill saidtube with a defined volume of powder; and c) transferring said definedvolume of powder from said tube.
 2. A method according to claim 1wherein the powder is compacted to between 10 and 99% of its originaldensity.
 3. A method according to claim 2 wherein the powder iscompacted to between 20 and 50% of its original density.
 4. A methodaccording to claim 1 wherein the compaction is achievable by the use ofa compaction pin.
 5. A method according to claim 1 wherein thecompaction is achievable by the use of a compaction plate.
 6. A methodaccording to claim 1 wherein the compaction is achievable by the use ofa dosator piston located within the tube such that at least a portion ofsaid dosator piston is essentially flush with or protrudes from thedipping end of the tube.
 7. A method according to claim 1 wherein thecompaction is achievable by the use of a dosator piston located withinthe tube such that at least a portion of said dosator piston isessentially flush with the dipping end of the tube.
 8. A methodaccording to claim 6 wherein said dosator piston is slidably retractablewithin the tube following compaction to create a cavity for filling withthe defined volume of powder.
 9. A method according to claim 1 whereinthe tube is tapered towards its dipping end.
 10. A method according toclaim 1, wherein said tube has an inner cross sectional area, andwherein the target area of powder is greater than the inner crosssectional area of the tube.
 11. A method according to claim 1 wherein,wherein said tube has an inner cross sectional area, and the target areaof powder is equal to the inner cross sectional area of the tube.
 12. Amethod according to claim 1 further comprising compacting the powder inthe tube subsequent to filling the tube with the defined volume ofpowder.
 13. A method according to claim 6 wherein the defined volume ofpowder is transferable from the tube by slidable movement of the dosatorpiston to eject the powder.
 14. A method according to claim 1additionally comprising transferring the powder to a container.
 15. Amethod according to claim 14 wherein the container is selected from thegroup consisting of a blister pocket, an injection moulded plasticpocket and a capsule.
 16. A method according to claim 1 additionallycomprising applying a seal to each end of the filled tube, subsequent todipping the tube into the compacted target area of powder.
 17. A methodaccording to claim 16 additionally comprising placing said sealed tubein a drug delivery system.
 18. A method according to claim 16additionally comprising piercing said seal immediately prior totransferring the defined volume of powder.
 19. A method according toclaim 18 wherein the piercing is achievable by the use of a piercingpin.
 20. A method according to claim 17 wherein said piercing pin formsan integral part of said drug delivery system.
 21. A method according toclaim 16 wherein the defined volume of powder is transferable from saidtube by use of a transferring pin to eject the powder into a drugdelivery system.
 22. A method according to claim 21 wherein saidtransferring pin forms an integral part of the drug delivery system. 23.A method according to claim 19 wherein the piercing pin and thetransferring pin are identical.
 24. A method according to claim 1additionally comprising levelling the powder prior to compaction.
 25. Amethod according to claim 24, wherein the levelling is achieved by theuse of a leveller blade movable on a linear sweeping path.
 26. A methodaccording to claim 25 wherein said leveller blade is perpendicular tosaid linear sweeping path.
 27. A method according to claim 25 whereinthe leveller blade presents a forward acute angle to the linear sweepingpath.
 28. A method according to claim 27 wherein said forward acuteangle is between 40 and 50°.
 29. A method according to claim 1additionally comprising disrupting the powder following removal of thedefined quantity of powder.
 30. A method according to claim 1 whereinthe powder comprises a medicament.
 31. A method according to claim 30wherein the medicament is selected from the group consisting ofalbuterol, salmeterol, fluticasone propionate and beclomethasonedipropionate and salts or solvates thereof and any mixtures thereof. 32.A method according to claim 31 wherein said mixture comprises salmeterolxinafoate and fluticasone propionate.
 33. A method according to claim 30wherein the powder further comprises an excipient.
 34. A methodaccording to claim 33 wherein the excipient is a sugar.
 35. A methodaccording to claim 1 wherein the powder is selected from the groupconsisting of an explosive powder, a sweetener, herbal product, foodsupplement and vitamin.
 36. An apparatus for transferring a definedquantity of powder which comprises; a) a powder reservoir containing abulk of powder; b) a tube suitable for containing a defined volume ofpowder, said tube having a dipping end; c) a compactor for compacting atarget area of powder within said bulk of powder, without compactingsubstantially all of the bulk of powder surrounding the target area ofpowder; wherein said compacted powder from said target area ispositionable within said tube to form a filled tube; and d) a transferorto transfer said defined volume of powder from said tube.
 37. Anapparatus according to claim 36 wherein the compactor comprises acompaction pin.
 38. An apparatus according to claim 36 wherein thecompactor comprises a compaction plate.
 39. An apparatus according toclaim 36 wherein the compactor comprises a dosator piston located withinthe tube such that at least a portion of said dosator piston isessentially flush with or protrudes from the dipping end.
 40. Anapparatus according to claim 36 wherein the compactor comprises adosator piston located within the tube such that at least a portion ofsaid dosator piston is essentially flush with the dipping end.
 41. Anapparatus according to claim 39 wherein said dosator piston is slidablyretractable within the tube to create a cavity for filling with thedefined volume of powder.
 42. An apparatus according to claim 36 whereinthe tube is tapered towards said dipping end.
 43. An apparatus accordingto claim 36, wherein said tube has an inner cross sectional area,wherein the target area of powder is greater than the inner crosssectional area of the tube.
 44. An apparatus according to claim 36,wherein said tube has an inner cross sectional area, wherein the targetarea of powder is equal to the inner cross sectional area of the tube.45. An apparatus according to claim 36 additionally comprising a sealapplier to apply a seal to each end of the filled tube to form a sealedtube, subsequent to dipping the tube into the compacted target area ofpowder.
 46. An apparatus according to claim 45 additionally comprising apiercer to pierce said seal immediately prior to transferring thedefined volume of powder.
 47. An apparatus according to claim 46 whereinthe piercer comprises a piercing pin.
 48. An apparatus according toclaim 47 wherein said piercing pin forms an integral part of a drugdelivery system.
 49. An apparatus according to claim 36 wherein thetransferor comprises a transferring pin.
 50. An apparatus according toclaim 49 wherein said transferring pin forms an integral part of a drugdelivery system.
 51. An apparatus according to claim 47 wherein thetransferor and piercing pin are identical.
 52. An apparatus according toclaim 36 wherein the transferor transfers the defined volume of powderto a container.
 53. An apparatus according to claim 52 wherein thecontainer is selected from the group consisting of a blister pocket, aninjection moulded plastic pocket and a capsule.
 54. An apparatusaccording to claim 52 wherein the transferor comprises the dosatorpiston which slidably moves within the tube to eject the powder.
 55. Anapparatus according to claim 36 additionally comprising a leveller tolevel the powder prior to compaction.
 56. A method according to claim55, wherein the levelling is achieved by the use of a leveller blademovable on a linear sweeping path.
 57. A method according to claim 56wherein said leveller blade is perpendicular to said linear sweepingpath.
 58. A method according to claim 57 wherein the leveller bladepresents a forward acute angle to the linear sweeping path.
 59. A methodaccording to claim 58 wherein the forward acute angle is between 40° and50°.
 60. An apparatus according to claim 36 additionally comprising adisrupter to disrupt the powder following removal of the definedquantity of powder.
 61. An apparatus according to claim 36 wherein thepowder comprises a medicament.
 62. An apparatus according to claim 61wherein the medicament is selected from the group consisting ofalbuterol, salmeterol, fluticasone propionate and beclomethasonedipropionate and salts or solvates thereof and any mixtures thereof. 63.An apparatus according to claim 62 wherein said mixture comprisessalmeterol xinafoate and fluticasone propionate.
 64. An apparatusaccording to claim 61 wherein the powder further comprises an excipient.65. An apparatus according to claim 64 wherein the excipient is a sugar.66. An apparatus according to claim 45 wherein the powder is selectedfrom the group consisting of an explosive powder, a sweetener, a herbalproduct, powdered food supplement and vitamins.
 67. A transferred powdersample obtainable by the method according to claim 1.